I am applying for an Individual Research Career Award ("K" series) in order to continue my training in the basic mechanisms of immune mediated diseases. It is my objective to become an independent investigator whose focus is on the fundamental mechanisms of gastrointestinal disease. At the same time, I plan to remain active in clinical medicine and teaching, in part to keep a clinical perspective with which to guide my basic research. I chose to do my postdoctoral fellowship in the laboratory of a basic immunologist, Dr. Abul K. Abbas, and under his guidance I will continue to develop as a basic scientist, while applying clinical insight to the formulation of hypotheses about the mechanisms of disease. In addition, my collaboration with Dr. Jeffrey Bluestone and my association with the UCSF Division of Gastroenterology will expose me to excellent role models and will provide me with an ideal environment in which to mature as a scientist. Inflammatory bowel disease (IBD) is an idiopathic inflammatory disorder of the GI tract. Its etiology is unknown but is thought to be multifactorial, involving interactions between genetic, environmental and immune factors. Recent evidence suggests that this disease is caused by a disruption in the mechanisms that normally regulate the immune response to luminal bacteria. CTLA-4 is a receptor located on the surface of T cells that attenuates T cell responses by inhibiting T cell proliferation and cytokine production. Despite its importance in the regulation of T cell-mediated immune responses, the biochemical mechanism by which CTLA-4 induces its effect remains unknown. In addition, recent evidence suggests that CTLA-4's attenuating effect may play a role in the prevention of IBD. The aims of this proposal are to determine how CTLA-4 acts in vivo to regulate the mucosal immune response to intestinal bacteria, and to define the biochemical pathways that mediate its effects in primary T cells.